Pemetrexed plus platinum outperforms other platinum-based adjuvant chemotherapy regimens for resected stage II–IIIA lung adenocarcinoma: an open-label, historical-control study

Introduction

Background

Lung cancer has been resulting in huge burden around the world. There were estimated 2.2 million new cases and 1.8 million deaths of lung cancer in 2020 worldwide (1). Lung cancer has been the most common cancer and leading cause of cancer both in males and in females within China according to the latest statistics (2). Non-small-cell lung cancer (NSCLC) comprises more than 85% of lung cancer. Adenocarcinoma is the most common histological subtype of NSCLC which accounts for 40% globally (3). Approximately only 30% of NSCLC patients have the opportunity to receive radical surgery when diagnosed (4), and with the widespread use of low-dose spiral computed tomography, an increasing number of patients are diagnosed at localized stage and have the opportunity to receive complete resection (5).

Rationale and knowledge gap

In the past two decades, radical operation and postoperative chemotherapy have been the standard treatment of stage II–IIIA NSCLC based on a series of clinical studies such as IATL and LACE study (6,7). In the LACE analysis, postoperative cisplatin-based chemotherapy resulted in a 5-year overall survival (OS) absolute benefit of 5.4% in patients with stage II–III NSCLC, and cisplatin combined with vinorelbine was the most acceptable therapeutic regimen (7). However, the severe adverse events (AEs) associated with cisplatin plus vinorelbine, such as neutropenia and phlebitis, restrict its clinical application. For nearly 10 years, researchers have made efforts to seek for the better NSCLC postoperative adjuvant chemotherapy regime which can balance safety and efficacy optimally. The TREAT study showed that cisplatin plus pemetrexed (PEM) regimen as the adjuvant chemotherapy was safer than cisplatin plus vinorelbine, while neither OS nor progression-free survival (PFS) differed between the two groups (8). Our team have previously published a retrospective study comparing the difference of DFS between PEM plus platinum and other platinum-based regimens with findings showing that PEM plus platinum group resulted in better DFS and less clinical toxicity compared with non-PEM based doublets in lung adenocarcinoma (9). However, JIPANG study from Japan about adjuvant chemotherapy published in 2020 showed that there was no significant difference in efficacy between PEM plus cisplatin and vinorelbine plus cisplatin in completely resected stage II to IIIA non-squamous NSCLC (10). Up to now, Platinum-based doublet chemotherapy remains the standard adjuvant treatment for patients with completely resected stage II–III lung adenocarcinoma. Among these regimens, PEM has shown superior efficacy and a more favorable toxicity profile in non-squamous NSCLC compared with other agents, as demonstrated by multiple phase III studies including the JIPANG trial. However, evidence remains limited regarding its effectiveness in broader, real-world cohorts, particularly in patients with stage II–III adenocarcinoma and when compared against non-PEM platinum-based regimens commonly used in clinical practice.

In recent years, adjuvant therapy strategies for early-stage NSCLC having received curative-intent surgery have undergone rapid development, with adjuvant immunotherapy and targeted therapy significantly improving patients’ survival outcomes. However, platinum-based adjuvant chemotherapy remains an essential component of postoperative treatment. In the IMpower010 trial, patients were required to receive adjuvant chemotherapy prior to initiating immunotherapy (11,12). Adjuvant chemotherapy was optional in KEYNOTE-091, while the subgroup analysis for patients not receiving adjuvant chemotherapy showed no benefit with the addition of pembrolizumab compared to placebo (13,14). In the ADAURA trial, subgroup analysis revealed that patients receiving adjuvant chemotherapy before osimertinib obtained a numerically better event-free survival (EFS) benefit [hazard ratio (HR) =0.29; 95% confidence interval (CI): 0.21–0.39] than patients not getting adjuvant chemotherapy (HR =0.36; 95% CI: 0.24–0.55). Besides, for patients with low programmed death-ligand 1 (PD-L1) expression or those who are mutation-negative, optimizing adjuvant chemotherapy remains of significant importance. Our study aimed to evaluate the real-world effectiveness of PEM plus platinum compared with non-PEM platinum-based regimens in patients with resected stage II–III lung adenocarcinoma, providing complementary evidence to existing randomized clinical trials.

Objective

Therefore, we performed this open-label, historical-control study to compare the efficacy and safety of PEM plus platinum with non-PEM plus platinum as the adjuvant chemotherapy regime for resected stage II–IIIA lung adenocarcinoma. Given that multiple studies have demonstrated significantly higher toxicity profiles with various non-PEM combined with platinum regimens (including vinorelbine) versus PEM-platinum chemotherapy, this study adopted a historical control design. This study prospectively enrolled patients who received PEM-platinum chemotherapy, while retrospective data were collected from historical cohorts treated with non-PEM platinum-based adjuvant regimens. This approach enabled comparative analysis of efficacy and AEs while avoiding unnecessary treatment-related toxicity in trial participants. We present this article in accordance with the TREND reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1060/rc).

Methods

Patients

Based on our preliminary retrospective study results (9), the 1-year DFS rate was approximately 70% in patients receiving postoperative adjuvant chemotherapy with PEM-platinum combination, compared to about 65% in those receiving non-PEM platinum-based regimens. Using statistical parameters of α=0.05 (two-sided) and β=0.1 (90% power), with an accrual period of 12 months and total study time of 36 months, and assuming a 1:3 allocation ratio between the PEM and non-PEM groups, the calculated sample sizes were 62 cases for the PEM group and 186 cases for the non-PEM group. Patients in PEM/platinum group were prospectively enrolled from those receiving treatment in Peking University Cancer Hospital including outpatients and inpatients, while those in non-PEM/platinum group were retrospectively collected as historical control from previous hospital medical records of Peking University Cancer Hospital, Cancer Hospital Chinese Academy of Medical Sciences and Peking University People’s Hospital. In the prospective group, eligible patients were age 18–75 years who underwent complete surgery within 4–8 weeks and were pathologically confirmed stage II–IIIA lung adenocarcinoma, complete contraception throughout the treatment until 4 weeks after the last therapy, without uncontrolled diabetes, having the ability of understanding and signing informed consent form. All patients were Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and satisfied adequate organ function. Key exclusion criteria were pathologically confirmed stage I, IIIB or IV adenocarcinoma, unstable systemic disease (e.g., active infection, uncontrolled hypertension, unstable angina, congestive heart-failure, active liver/kidney disease or metabolic disease), having other malignant tumors within 5 years, nervous system disease or psychiatric disease, women who were pregnant or breastfeeding, any situations threatening patients’ safety and compliance and conditions that clinicians found inappropriate. In the retrospective group, we enrolled patients with pathologic stage II–IIIA lung adenocarcinoma who underwent radical resection between January 2003 and December 2021, and received non-PEM plus platinum as adjuvant chemotherapy regime. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments and was approved by the Ethics Committee of Peking University Cancer Hospital (approval No. 2018KT81). All the prospective patients signed informed consent. For this retrospective analysis of anonymized patient data, the requirement for informed consent was waived by the committee.

Procedures

All enrolled patients in the prospective cohort received PEM combined with platinum adjuvant chemotherapy [cisplatin (75 mg/m²) or carboplatin (area under the curve =5) and PEM (500 mg/m²) by intravenous infusion every 3 weeks for 4 cycles]. During PEM treatment, folic acid supplementation (400 µg orally once daily) was initiated 5 days prior to the first dose and continued throughout therapy until 21 days after the last PEM treatment. Additionally, vitamin B12 (1,000 µg, intramuscular injection) was administered on the day of the first PEM dose and repeated every three cycles thereafter; subsequent injections could be scheduled on the same day as PEM administration. After the physician issues the prescription, the nursing staff administers the medical treatment as ordered. After chemotherapy, adjuvant radiation therapy was administrated in patients having positive margin or multiple station mediastinal lymph nodes metastasis. The first assessment was conducted when the 4 cycles of chemotherapy was completed. After that, patients were asked to review every 12 weeks in the first years, and every 24 weeks after the second year until progression of disease. After the completion of the research, investigators would keep on recording the assessment results of patients every 24 weeks to collect survival information. All the retrospective patients received non-PEM plus platinum as adjuvant chemotherapy including paclitaxel, gemcitabine and vinorelbine. We collected clinical characteristics, efficacy data (DFS) and AEs during adjuvant treatment of these patients. Streamlining study procedures (such as telephone follow-up) and promptly addressing patients’ needs were utilized to enhance patients’ treatment adherence. Study data were extracted from the Hospital Information System.

Outcomes

The primary end point of this study was DFS, which was defined by the time from surgery to recurrence confirmed by image or death before recurrence from any cause. The last data of disease assessment was the final follow-up time for people who were still alive and did not recur at the time of final analysis. Progression of disease was assessed based on Response Evaluation Criteria in Solid Tumors (RESIST) 1.1 by investigators. All patients who had received adjuvant chemotherapy at least once were concerned as study population to analyze safety. The secondary endpoint was AEs. All the AEs were reported and graded by Common Terminology Criteria of Adverse Events (CTCAE) 4.0.

Statistical analysis

All statistical analysis was performed using R software4.4.2. Descriptive statistics were used to summarize baseline characteristics. Kaplan-Meier method was used to estimate event time. Univariate analyses were performed by using the log-rank test. HRs with 95% CIs were calculated using univariate and multivariate Cox proportional hazards regression models; variables with P<0.10 in univariate analyses or deemed clinically relevant were included in multivariate models. Propensity score matching (PSM) was utilized to minimize potential confounding. Matching variables included sex, age, pathological stage, smoking, surgery and ECOG performance status. The grouping variable was PEM treatment (received/not received). Following propensity score alignment using greedy algorithm, patients from both cohorts demonstrating balanced scores were paired 1:1 through non-replacement selection.

Results

Patients

In the prospective cohort, a total of 71 pathologic stage II–IIIA lung adenocarcinoma patients were enrolled who were all received PEM combined with platinum adjuvant chemotherapy between June 2018 and July 2022 from Beijing Cancer Hospital (Figure 1). In the historical control cohort, we retrospectively included 209 stage II–IIIA lung adenocarcinoma patients who underwent radical surgery and received non-PEM plus platinum postoperative adjuvant chemotherapy treated in Beijing Cancer Hospital, Cancer Hospital Chinese Academy of Medical Sciences and Peking University People’s Hospital from 2003 to 2021 (Figure 1). Baseline characteristics of all patients were presented in Table 1.

Figure 1 Flow chart for selection of patients. AEs, adverse events; NSCLC, non-small cell lung cancer; PEM, pemetrexed.

DFS outcome in PEM group and non-PEM group

During a median follow-up of 45.6 months (interquartile range, 40.3–55.7 months) through September 8, 2025, 35 of 71 prospective patients recurred and the 2-year DFS was 67.61%. The median DFS was not reached. In contrast, in the non-PEM plus platinum group, 161 of 209 patients relapsed, and the median DFS was 18.9 months (95% CI: 15.6–22.0). The final analysis was performed using the intention-to-treat (ITT) population.

Figure 2 showed that DFS in prospective PEM plus platinum group was significantly better than retrospective non-PEM plus platinum group (P<0.001, HR =0.499; 95% CI: 0.345–0.72). In the univariable Cox analysis, treatment regimen (PEM vs. non-PEM) and pathological stage were significantly associated with DFS (Table 2). Multivariable Cox regression analysis was performed to identify independent prognostic factors for DFS, and the results were summarized in a forest plot (Figure 3). Among these variables, pathological stage remained a significant determinant of DFS, underscoring its critical role in postoperative risk stratification. Given the potential difference in the baseline characteristics of the two groups, PSM was used to generate comparable study cohorts. After 1:1 matching, 74 patients were ultimately included (37 in the PEM group and 37 in the non-PEM group). After PSM based on age, sex, pathologic stage, smoking status, surgery and ECOG, the two groups were well-matched. Comparison of baseline characteristics between patients before and after matching is shown in Table 3. Notably, patients who received PEM plus platinum as adjuvant chemotherapy still showed better DFS than the non-PEM plus platinum group (P=0.01, HR =0.479; 95% CI: 0.268–0.858) (Figure 4).

Figure 2 Kaplan-Meier curves of DFS comparison between PEM and non-PEM groups before PSM. CI, confidence interval; DFS, disease-free survival; HR, hazard ratio; PEM, pemetrexed; PSM, propensity score matching.

Figure 3 Multivariable Cox regression analysis for DFS. DFS, disease-free survival; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio.

Figure 4 Kaplan-Meier curves of DFS comparison between PEM and non-PEM groups after PSM. CI, confidence interval; DFS, disease-free survival; HR, hazard ratio; PEM, pemetrexed; PSM, propensity score matching.

Subgroup analysis of DFS based on EGFR status in PEM group

In the prospective PEM cohort of 71 patients, we performed a subgroup analysis based on EGFR mutation status. Among them, 36 patients harbored an EGFR mutation [including 5 who received EGFR-tyrosine kinase inhibitor (TKI) therapy following adjuvant chemotherapy], and 35 were EGFR wild-type. The analysis revealed no significant difference in DFS between the EGFR-mutant and EGFR wild-type subgroups (P=0.91; HR =0.96, 95% CI: 0.50–1.87) (Figure 5A). After excluding the 5 patients who received EGFR-TKI treatment after adjuvant chemotherapy, DFS remained comparable between the remaining EGFR-mutant and wild-type patients (P=0.89; HR =0.95, 95% CI: 0.48–1.88) (Figure 5B).

Figure 5 Kaplan-Meier curves of DFS comparison between EGFR wild-type vs. EGFR mutation subgroups (A) and between EGFR wild-type vs. EGFR mutation no-TKI (B). CI, confidence interval; DFS, disease-free survival; HR, hazard ratio; TKI, tyrosine kinase inhibitor.

Safety

In the PEM plus platinum group, most of the patients could tolerate adjuvant chemotherapy well, and all the AEs were shown in Table 4. The common AEs were neutropenia (25.4%), leukopenia (22.5%) and nausea (15.5%). One patient (1.4%) developed grade 3/4 leukopenia and 1 patient developed grade 3/4 arrhythmia (Table 3). While in the non-PEM plus platinum group, the common AEs were nausea (85.2%), neutropenia (76.1%) and anemia (48.3%). Grade 3/4 AEs were mainly hematologic toxicities (Table 4). No treatment-related death occurred in both of two groups. Overall AEs occurred more frequently in non-PEM plus platinum group. Hematological toxicities were the most common AEs in both groups, whereas nausea, vomiting and alopecia were obviously higher in non-PEM/platinum group.

Discussion

Five-year survival rate of lung adenocarcinoma varies obviously depending on clinical stage at the time of diagnosis. The 5-year OS ranges from 83% for stage IA to 36% for stage IIIA disease, while that is only 6% in patients who are diagnosed with distant metastases (15). Therefore, early diagnosis and the most appropriate treatment—the best perioperative treatment and the choice of type of surgical—are crucial to prolonging survival in early-stage lung cancer. In the past five years, plentiful positive trial results have revolutionized the clinical setting of early-stage, resectable NSCLC including adjuvant targeted therapies, immunotherapies and perioperative therapy (16). However, adjuvant chemotherapy still plays an essential role. The ADAURA trial showed that adjuvant osimertinib provided a significant OS benefit among patients with completely resected, EGFR-mutated, stage IB–IIIA NSCLC (17). While a closer look at OS for patients with pathologic stage II–IIIA showed that patients who received adjuvant chemotherapy and osimertinib had a 5-year OS of 87% vs. 80% with osimertinib alone alluding that adjuvant chemotherapy might be more important for more advanced-stage disease (16). OS analysis of IMpower 010 indicates a positive trend favouring atezolizumab after adjuvant chemotherapy in PD-L1 positive subgroup analyses, primarily driven by the PD-L1 tumor cell ≥50% stage II–IIIA subgroup (18).

In this study, we conducted an open-label, historical-control study to compare the efficacy and safety of PEM combined with platinum and non-PEM plus platinum as adjuvant chemotherapy. The 2-year DFS of PEM plus platinum was 67.61%, and the median DFS was not reached. Most of the AEs were grade 1/2 showing this regime was well tolerated. Published studies have suggested that non-PEM platinum-based doublet regimens (e.g., vinorelbine or paclitaxel) (9,10) are associated with a higher incidence of adverse reactions compared to PEM-platinum combinations. Therefore, to minimize unnecessary harm to patients, we adopted a historical control study design, selecting previously hospitalized patients who received non-PEM regimens as the control group. The median DFS of historical control group was 18.9 months (95% CI: 15.6–22.0). We adopted PSM to balance potential confounding factors to compare the DFS of different regimes. The DFS of PEM plus platinum group was significantly better than non-PEM plus platinum group before (P<0.001) and after (P=0.01) PSM. Besides, PEM/platinum regime was better tolerated than non-PEM plus platinum. Non-PEM group including paclitaxel, docetaxel, gemcitabine and vinorelbine were more likely to cause hematological toxicity, gastrointestinal AEs and alopecia. Nevertheless, higher frequency of gastrointestinal AEs might be related to the more usage of cisplatin. In conclusion, our study indicates that PEM plus platinum is a more appropriate adjuvant chemotherapy regime for radically resected lung adenocarcinoma.

There have been some studies attempting to find the most appropriate postoperative adjuvant chemotherapy regime in respectable NSCLC. A randomized phase III study from Japan found that PEM plus cisplatin could not bring efficacy superiority compared with vinorelbine plus cisplatin but showed a better tolerability (10). The Japanese study employed only vinorelbine as the control scheme, whereas our study collected all non-PEM agents as control regimens; this can explain why our study reached a different conclusion. Some researchers intended to utilize gene detection to guide adjuvant chemotherapy which was called tailored chemotherapy. In the International Tailored Chemotherapy Adjuvant trial (ITACA), stage II–IIIA resected NSCLC patients received pharmacogenomic-driven chemotherapy according to the ERCC1 and TS genes expression profile or standard platinum-based doublets (19). The results of the ITACA showed that there was no difference both in OS and in recurrence-free survival (RFS) between pharmacogenomic-driven chemotherapy and standard chemotherapy. Other trials based on pharmacogenomic-driven chemotherapy also did not reach positive results (20,21). Unlike those trials, the results of our study indicated that PEM plus platinum might be the optimal regime as adjuvant chemotherapy in resected lung adenocarcinoma patients.

It is noteworthy that in the PEM group of this study, more than half of the patients were treated with carboplatin rather than cisplatin. While cisplatin-based chemotherapy has long been the standard for adjuvant therapy, previous evidence has shown that carboplatin-based doublet regimens yield comparable efficacy in advanced non-small cell lung cancer (22,23). It is crucial to emphasize that cisplatin is frequently associated with significant renal, gastrointestinal, and neurotoxicity, which often limit its tolerability in clinical practice. Carboplatin, with its more favorable safety profile, is often the preferred choice—particularly for patients with impaired renal function or multiple comorbidities. Therefore, the conclusions of our study extend those of the JIPANG trial, demonstrating that the combination of PEM and carboplatin is also effective and better reflects real-world clinical practice patterns.

However, there are some limitations in this study. Firstly, next-generation sequencing (NGS) was performed only in the prospective PEM cohort, whereas the non-PEM group did not undergo uniform comprehensive genetic testing. Therefore, exhaustive genomic profiling was not conducted, and we cannot exclude the possibility that untested genomic alterations may have influenced treatment response or prognosis. We could only evaluate the prognostic impact of EGFR mutations in the prospective cohort. A subgroup analysis of all 71 patients revealed no significant association between EGFR mutation status and DFS (P=0.91, HR =0.96, 95% CI: 0.50–1.87). In the prospective cohort, five patients initiated oral EGFR-TKI therapy immediately following postoperative adjuvant chemotherapy. After excluding these five cases, EGFR mutation status remained not significantly associated with DFS. This suggests that EGFR mutation status primarily predicts benefit from EGFR-TKI therapy, while its prognostic role in the natural disease course or in platinum-based adjuvant chemotherapy may not be significant. Regardless, the lack of EGFR status in the control group limits direct comparisons between groups and may introduce potential confounding. Given the established higher value of postoperative adjuvant chemotherapy in patients with driver-gene negative lung adenocarcinoma as determined by comprehensive genomic profiling, well-designed randomized controlled trial could be conducted to evaluate the potential superiority of PEM plus platinum chemotherapy over other platinum-doublet regimens in this patient population in the future. Another notable limitation is the potential influence of temporal bias inherent in historical control studies, which is difficult to avoid entirely. The use of a historical control cohort spanning 2003 to 2021 may introduce temporal bias, as advances in surgical techniques, diagnostic imaging, and supportive care over this period could have improved patient outcomes independent of chemotherapy regimens. For instance, the widespread adoption of minimally invasive surgery and standardized lymph node dissection has reduced postoperative morbidity, while modern imaging modalities such as positron emission tomography-computed tomography have enabled more accurate staging and earlier detection of recurrence. Nonetheless, we explicitly acknowledge this limitation and recommend that future studies employ concurrent controls or prospective randomized designs to better account for potential temporal confounding. Furthermore, DFS and OS data in the present study remain immature. Continued follow-up is underway to enable more robust survival analyses in subsequent investigations.

Conclusions

In this study, we found that PEM combined with platinum provided more satisfactory efficacy and clinical tolerability as adjuvant chemotherapy for pathologic stage II–IIIA lung adenocarcinoma patients than non-PEM plus platinum regime. Up till the present moment, PEM combined with platinum is still a superior regime for lung adenocarcinoma patients who need postoperative adjuvant chemotherapy.

Acknowledgments

We gratefully recognize all medical staff involved in these patients’ treatment.

Footnote

Reporting Checklist: The authors have completed the TREND reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1060/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1060/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1060/prf

Funding: This work was supported by Beijing Municipal Science & Technology Commission (No. Z181100001718104).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1060/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments and was approved by the Ethics Committee of Peking University Cancer Hospital (approval No. 2018KT81). All the prospective patients signed informed consent. For this retrospective analysis of anonymized patient data, the requirement for informed consent was waived by the committee.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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